Panitumumab Plus Trifluridine-Tipiracil as Anti–Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory <i>RAS</i> Wild-Type Metastatic Colorectal Cancer
Authors: Stefania Napolitano, Vincenzo De Falco, Giulia Martini, Davide Ciardiello, Erika Martinelli, Carminia Maria Della Corte, Lucia Esposito, Vincenzo Famiglietti, Alessandra Di Liello, Antonio Avallone, Claudia Cardone, Alfonso De Stefano, Vincenzo Montesarchio, Maria Giulia Zampino, Roberto Bordonaro, Mario Scartozzi, Daniele Santini, Massimo Di Maio, Ferdinando De Vita, Lucia Altucci, Francesca Marrone, Fortunato Ciardiello, Teresa Troiani
Journal: JAMA Oncology (2023)

Importance Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients. Objective To compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC. Design, Setting, and Participants This phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug–free interval of 4 or more months during second-line therapy were included. Interventions Patients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone. Main Outcomes and Measures The primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients. Results Of 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS , NRAS , BRAFV600E , EGFR , ERBB2 , MAP2K1 , and PIK3CA , median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response. Conclusions and Relevance In this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy–guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC. Trial Registration ClinicalTrials.gov Identifier: NCT05468892